ABSTRACT: Withdrawal of Hydroxychloroquine (HCQ) in Elderly Lupus Patients This R34 planning grant application is driven by the need to establish evidence-based protocols for the management of aging lupus patients, a topic that has received minimal attention to date. Thus, clinical equipoise is needed to better assess elderly patients with stable SLE to more accurately weigh the balance between accumulating ocular exposure and the explosion of new tools to assess retinal injury versus the risk of disease flare in a population that may have more inactive disease than younger patients. Despite a track record of safety with regard to infection compared to traditional immunosuppressive agents, the risk of HCQ retinal toxicity escalates with continued use. Evaluation using sensitive approaches suggests nearly a third of patients accrue retinal damage. The decision to discontinue HCQ is difficult but timely, especially in patients who have been stable and on the medication for years. As the longevity of lupus patients improves, which may increase comorbidities that affect HCQ clearance (e.g., renal insufficiency), the ratio of efficacy to toxicity would be expected to decrease. That disease activity may wane in the aging population drives the ratio down even further. The purpose of this R34 is to provide support for the planning, design and subsequent implementation of a randomized, controlled multicenter Phase III double-blind non-inferiority trial to address the safety of withdrawal of HCQ in SLE patients ?60 years old. The central hypothesis is that HCQ can be safely discontinued in stable/quiescent patients assessed by validated disease activity and flare instruments and serologic, cellular, and cytokine profiling. Per the preliminary study design being planned, the primary outcome is the number of patients in each group who develop a moderate/severe flare during follow-up. Based on the projection of a 13% flare rate in patients remaining on HCQ and an acceptable rate up to 23% in those who withdraw (i.e., non-inferiority margin of 10% absolute difference between groups), target enrollment is 165 patients per arm (total 330) followed bi-monthly for 12 months. Eligible patients will have been taking HCQ for ?7 years, with compliance assessed by HCQ levels. To provide robust evidence generalizable across diverse ethnic/racial populations and socioeconomic strata, 7 institutions (NYU, HSS, Columbia, Penn State, UCLA, OMRF, Einstein) comprise the core clinical investigative team. This study will be leveraged to provide insights into aging of the immune system and its effects on autoimmunity. Trial infrastructure will be established in compliance with NIH guidelines, and completion of the following deliverables: study protocol with inclusion of biomarker studies and comprehensive biostatistical analysis plan; manual of operating procedures; electronic data capture system; data management plan; acquisition of study drugs; training of support staff; submission of regulatory documents for IRB approval; performance of model recruitment; and a U01 submission. It is anticipated that this trial will significantly impact the care of our aging lupus population and provide a molecular landscape of autoimmune parameters that may identify patients appropriate for medication adjustments.